Amyloid diseases or amyloidoses are diseases involving amyloidogenesis, amyloid formation or aggregation of amyloid proteins in certain body tissues, often linked with cytotoxic effects. For instance, Alzheimer's disease involves amyloidogenesis of the β-amyloid peptide (β-AP).
It is assumed that the development of amyloid deposits of various peptides is responsible for occurrence and pathologic complications of amyloid diseases (Lorenzo et al., Nature 368 (1994), 756-760; Lorenzo et al., Proc. Nat'l. Acad. Sci. USA 91 (1994), 12243-12247; Lansbury et al., Proc. Nat'l. Acad. Sci. USA 96 (1999), 3342-3344; Koo et al., Proc. Nat'l. Acad. Sci. USA 96 (1999), 9989-9990; Sipe et al., Critical Reviews in Clinical Laboratory Sciences 31(4) (1994), 325-354. It is further assumed that inhibitors of amyloid formation are suitable pharmaceuticals for prophylaxis and treatment of the amyloid diseases.
Linear peptides of 3 to 15 amino acids which can act as agonists and/or inhibitors of amyloid formation are known from DE-A1 197 25 619. These peptides are distinguished by the fact that they contain at least the amino acids GA as the active sequence.
Peptides which modulate β-amyloid aggregation are known from U.S. Pat. No. 5,854,204. These are linearly constructed peptides of different lengths which are derived particularly from the β-amyloid precursor protein 770.
WO 96/39834 describes other linear peptides which can cure diseases with abnormal peptide aggregation. The peptides described have 3 to 15 amino acids, a hydrophobic segment of 3 amino acids and, in this hydrophobic segment, at least one amino acid which blocks a β-pleated sheet structure.
WO 96/07425 describes neurotoxic effects of the amyloid β-protein due to inhibiting synthetic peptides with linear structure. Diagnosis and treatment of Type II Diabetes mellitus using Amylin and derivatives of it is described n EP 0 289 287 and EP 0 309 100 A2.
Test procedures for early detection of amyloid diseases are not yet available, or are only in the development stage. That is because the problems of protein chemistry and technical analysis caused by amyloid formation have not yet allowed any analysis of amyloid formation. Because of that, the mechanism of amyloid formation is essentially unexplained. As a further result, there are not at present any pharmaceutical preparations for treatment of the amyloid diseases on the basis of modulators, especially inhibitors, of amyloidogenesis. Likewise, there are very few diagnostic procedures based on analysis of amyloid development, such as in vitro tests for evaluation of the kinetics, quantity and quality of formation of amyloid structures. The diagnosis still must be done symptomatically, as for Alzheimer's disease, for instance.
There is, in particular, need for suitable probes which can detect amyloid-forming peptides so as to determine abnormal increases in the concentration of amyloidogenic peptides among possible diseases. The problem for making such probes has been that the probes themselves must not aggregate, but still must interact specifically, i. e., bind, with the amyloidogenic peptides. The requirements for an inhibitor of amyloid formation will be similar. Also, such a substance obviously must not promote aggregation or aggregate itself, and it should also be able to bind the amyloidogenic peptides specifically to prevent further aggregation. It has not yet been possible to utilize any of the substances meeting the criteria listed above in medical diagnosis or therapy. There is, then, a great need for preparation of substances which can serve both as probes for diagnosis, particularly early detection, of diseases involving amyloid formation and for therapy, including prophylaxis, of such diseases.